The hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide. Poor responsiveness and limited access to drug treatment has prompted efforts to develop an effective HCV vaccine. Studies support that immune control of HCV is possible, with CD8+ cytotoxic T cells (CTL) playing a key role in governing the outcome of acute HCV infection in both humans and chimpanzees. There is significant evidence for the role that CD8+ CTL play in the containment of other highly variable pathogens such as HIV and SIV. However, it is becoming increasingly evident that the propensity of these pathogens to mutate and escape from these responses represents a substantial hurdle. Whereas viral escape from CD8+ CTL responses has been illustrated in the chimpanzee model of HCV infection, the ability of HCV to selectively escape from host CD8+ CTL in humans remains unclear. Recent reports have begun to elucidate the impact of immune selection pressures on shaping the global sequence diversity of highly variable pathogens such as HIV. There is also an increasingly clear role of specific HLA alleles and immune control of highly variable pathogens such as HIV, SIV and HCV which may be related to specific adaptations of the pathogen to other HLA alleles. Therefore, identifying HLA-associated sequence polymorphisms in chronic HCV infection represents a first step towards elucidating the relationship between MHC alleles, CD8 responses, viral diversity and control of HCV. Viral evolution also provides unique insights into immune control. High avidity CD8 T cell responses, found to be exceptional in their ability to control a viral infection, have been associated with rapid viral evolution. Similarly, reversion of CD8 escape mutations upon transmission has been observed and supports an impact of CD8-associated selective pressures on viral fitness. Therefore, characterizing the kinetics of CD8 escape, and the maintenance and frequency of these mutations in the population, may aid in the selection of efficacious CD8 T cell responses against HCV. The proposed project, therefore, will use whole HCV genome sequencing along with cellular assays to address the impact of viral diversity on immune control, elucidate the role of immune pressures in driving this diversity, and to identify important immune targets for design of an effective HCV vaccine.